Polychlorinated biphenyls (PCBs) are known to reduce serum thyroxine (T(4)) in rats, but the relative effects of individual PCB congeners on thyroid hormones are not known. Thus, male Sprague-Dawley rats were administered Aroclor 1254, Aroclor 1242 (4, 8, 16, or 32 mg/kg/day), PCB 95 (2,2',3,5',6-pentachlorobiphenyl), PCB 99 (2,2',4,4',5-pentachlorobiphenyl), PCB 118 (2,3',4,4',5-pentachlorobiphenyl) (2, 4, 8, or 16 mg/kg/day), PCB 126 (3,3'4,4',5-pentachlorobiphenyl) (2.5, 5, 10, 20, or 40 microg/kg/day), TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) (0.14, 0.43, 1.3, or 3.9 microg/kg/day), or corn oil via oral gavage for 7 days. Rats were necropsied 24 h after the last dose. Serum thyroid hormone levels were evaluated by radioimmunoassay, and induction of hepatic Cyp1a (a TCDD-inducible protein) and Cyp2b (a phenobarbital [PB]-inducible protein) activity was determined by ethoxyresorufin-O-deethylase and pentoxyresorufin-O-deethylase assays, respectively. Significant increases in Cyp1a activity occurred in response to PCBs, except PCB 95 and PCB 99. Aroclor 1254, PCB 99, and PCB 118 significantly induced Cyp2b activity. Serum total T(4) and free T(4) were dramatically reduced in response to each of the seven treatments in a dose-dependent manner. The marked T(4) reductions occurred in response to Aroclor 1254, PCB 99 (a PB-type congener), and PCB 118 (a mixed-type congener). In contrast, reductions in serum triiodothyronine (total and free) were variable and mild, and serum thyroid-stimulating hormone was not significantly affected by any of the compounds. These data indicate that the PB and mixed-type PCB congeners are more effective than the TCDD-type PCB congeners at reducing serum T(4).
A 4 mg dose of beclomethasone‐17,21‐dipropionate‐16,16a‐3H(BP2‐16‐3H) has been given orally in a capsule to 4 subiects, and 2 further subjects as a micrafine suspension. The plasma levels of radioactivity reached a peak at 3 to 5 hours equivalent to 9.6 to 15.2 ng BP2‐16‐3H per milliliter in the capsule‐treated subjects, and 20 ng BP‐16‐3H per milliliter in the subjects given the suspension. Ten to fifteen per cent of the administered dose of radioactivity was excreted in the urine as both unidentified conjugated and free metabolites of the steroid. Fram radiochemical and chromatographie analyses of the feces it was estimated that 90% of the drug in the microfine suspension was absorbed compared with 61 % to 76% of that in the capsule formulation. In vitra BP2‐16‐3H was hydrolyzed by tissue and fecal esterases to beclomethasone‐17‐ propionate‐16,16a‐3H and beclomethasone‐16,16a‐3H. This study has shown that the swallowed portion of an aerosol of beclomethasone dipropionate would be absorbed fram the gastraintestinal tract, and that the lack of suppressive activity on the hypothalamo‐pituitary‐adrenal (HPA) axis of patients on therapeutic doses of the aerosolized steroid is not due to malabsorption of the drug.
In healthy normal subjects following the administration of labetalol the pharmacological effects were measured and compared with the plasma concentrations achieved. The inhibition of exercise induced tachycardia and inhibition of exercise induced increases in systolic pressure were significantly related to the administered dose of labetalol. Labetalol was rapidly absorbed from the gastrointestinal tract and peak plasma concentrations occurred two hours after oral administration. There was a linear correlation (r = 0.84) between the logarithm of the plasma concentration and the maximum inhibition of exercise tachycardia at two hours. After intravenous administration there was an immediate reduction in systolic and diastolic blood pressure with a concomitant small increase in heart rate. There was a rapid decline in the associated plasma concentration but the pharmacological effects were maintained in excess of two hours. Our findings are consistent with those of others who have studied the relationship between pharmacological events and plasma concentrations after single doses of other adrenoceptor blocking drugs.
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